Resveratrol displays converse dose-related effects on 5-fluorouracil-evoked colon cancer cell apoptosis - The roles of caspase-6 and p53 (Publication with Expression of Concern. See vol. 21, pg. 767, 2020)

We have reported that resveratrol (RSV) evoked apoptosis through caspase-6 activation in HCT116 human colon cancer cells wild-type (p53(+/+)) or knockout (p53(-/-)) for p53. In this study, the role of caspase-6 activation in 5-fluorouracil (5-FU)-elicited apoptosis as well as the combination effects between RSV and 5-FU on their apoptosis induction was further investigated in the same colon cancer cell model. The combination effects were determined by calculation of combination indices (CI). We found that 5-FU triggered apoptosis and caspase-6 activation in the cancer cells, which were entirely abrogated by caspase-6 inhibitors. RSV (200 mu M) increased 5-FU-triggered apoptosis and caspase-6 activation. Lower doses (25 or 50 mu M) inhibited 5-FU-mediated apoptosis and caspase-6 activation only in p53(+/+) cells. Moreover, G(1)-arrest of the p53(+/+) cells was elicited by lower doses of RSV and 5-FU in combination, but not with either agent alone. RSV (200 mu M) interacted with 5-FU in a synergistic manner (mean CI < 0.9). At lower doses (25 or 50 mu M), it interacted with 5-FU in antagonistic (mean CI > 1.1) and additive manners (0.9 < mean CI < 1.1) in p53(+/+) and p53(-/-) cells respectively. In conclusion, our results suggest that, like RSV, 5-FU triggers the cancer cell apoptosis by activating caspase-6. Their combination effect in apoptosis induction is dependent on the concentration of RSV and is mediated by caspase-6 activation. RSV synergistically promotes 5-FU-mediated apoptosis at its higher concentration irrespective of p53. Conversely, it inhibits 5-FU-triggered apoptosis at lower concentrations in p53(+/+) cells.